1. Field of the Disclosure
This disclosure relates generally to methods for synthesizing pirfenidone. More specifically, this disclosure relates to a process for preparing pirfenidone using a bromobenzene reagent having less than about 0.15% by weight dibromobenzene and using copper(I) oxide as a catalyst, instead of a copper (I) or (II) halide.
2. Brief Description of the Related Art
Pirfenidone is a non-peptide synthetic molecule with a molecular weight of 185.23 daltons. Its chemical elements are expressed as C12H11NO, and its structure is known. The synthesis of pirfenidone has been worked out. Pirfenidone is manufactured and being evaluated clinically as a broad-spectrum anti-fibrotic drug. Pirfenidone has anti-fibrotic properties via: decreased TNF-α expression, decreased PDGF expression, and decreased collagen expression. Several pirfenidone Investigational New Drug Applications (INDs) are currently on file with the U.S. Food and Drug Administration. Phase II human investigations have been initiated or completed for pulmonary fibrosis, renal glomerulosclerosis, and liver cirrhosis. There have been other Phase II studies that used pirfenidone to treat benign prostate hypertrophy, hypertrophic scarring (keloids), and rheumatoid arthritis.
One important use of pirfenidone is known to be providing therapeutic benefits to patients suffering from fibrosis conditions such as Hermansky-Pudlak Syndrome (HPS) associated pulmonary fibrosis and idiopathic pulmonary fibrosis (IPF). Pirfenidone demonstrates a pharmacologic ability to prevent or remove excessive scar tissue found in fibrosis associated with injured tissues including that of lungs, skin, joints, kidneys, prostate glands, and livers. Published and unpublished basic and clinical research suggests that pirfenidone may safely slow or inhibit the progressive enlargement of fibrotic lesions, remove pre-existing fibrotic lesions, and prevent formation of new fibrotic lesions following tissue injuries.
It is understood that one mechanism by which pirfenidone exerts its therapeutic effects is by modulating cytokine actions. Pirfenidone is a potent inhibitor of fibrogenic cytokines and TNF-α. It is well documented that pirfenidone inhibits excessive biosynthesis or release of various fibrogenic cytokines such as TGF-β1, bFGF, PDGF, and EGF. Zhang S et al., Australian New Eng. J. Ophthal., 26:S74-S76 (1998). Experimental reports also show that pirfenidone blocks the synthesis and release of excessive amounts of TNF-α from macrophages and other cells. Cain et al., Int. J. Immunopharm., 20:685-695 (1998).
Pirfenidone has been studied in clinical trials for use in treatment of IPF. Thus, there is a need for a synthetic scheme that provides pirfenidone having sufficient purity as an active pharmaceutical ingredient (API) and involves efficient and economical processes. Prior batches of pirfenidone were shown to have residual solvent traces of ethyl acetate (e.g., about 2 ppm) and butanol.